Despite advances in the treatment, infectious diseases remain a significant factor in worldwide mortality and morbidity. Mortality has risen and the emergence and re-emergence of diseases such as acquired immunodeficiency syndrome, Ebola virus, hantavirus, and tuberculosis demonstrate that the dangers of infectious disease are not static. The role of infectious disease in the etiology of diseases once believed to be non-infectious is only now being recognized. For example, the causative agent of peptic ulcers was only recently discovered to be a bacteria species termed Helicobacter pylori. Medical advances against infectious disease have also been hindered by changes in the patient population. The most susceptible group of individuals to infectious disease are immuno-compromised as a result of immuno-suppressant treatment for organ transplant, individuals undergoing chemotherapy, or most notably those infected by HIV.
The principle agent behind biological weapons is infectious disease. The bacteria Bacillus anthracis has appeared on World Health Organization lists for bioterrorism agents, and it has been reported that 50 kg of the bacillus released up wind of a city of 500,000 would result in over 95,000 fatalities and the incapacitation of 125,000 individuals. Smallpox, Yersinia pestis (plague), Francisella tularensis (tularemia), and viral hemorrhagic agents such as Ebola and Marburg viruses are also potential biological weapons.
While treatment for many infectious diseases does exist, rapid and simple diagnostics are needed in order to avoid death or significant complications. Unfortunately the majority of detection methods rely on microscopic visualization and culturing of the pathogen in order to obtain enough phenotypic data to differentially diagnose the infectious disease. These methods are imprecise, time consuming, and rely on highly-trained laboratory personnel. Other methods and systems that exist for diagnosis of some pathogens include: biological signals (unique or toxic components of a microorganism are differentiated from the normal physical environment); detection systems (used to sense a signal and discriminate between the signal and background noise; a detector can range from a trained set of eyes to sensitive electronic instruments designed to detect immunofluorescence, chemiluminescence, light absorbance, flame ionization detection, etc); and, amplification (techniques include polymerase chain reaction, which is able to detect and amplify sufficient unique pathogen DNA or RNA to allow for sensitive analysis and discrimination).
By way of example, protozoan pathogens are responsible for a wide variety of infectious diseases, typically tropical in nature. These pathogens exist as intracellular parasites in a host and include organisms that appear to be protozoan in nature such as Pneumocystis. An example of such protozoan pathogens is the genus Leishmania, which causes a spectrum of tropical and subtropical diseases known as the leishmaniases. Leishmania live as either extracellular, flagellated promastigotes in the digestive tract of their sand fly vector or as non-flagellated amastigotes within macrophages, where they survive and replicate within phagolysosomes. During both the innate and acquired immune responses, macrophages respond to extracellular signals to become activated for enhanced antimicrobial activity. This is a critical step in elimination of intracellular pathogens by the host. However, leishmania and other intracellular pathogens have developed mechanisms to interfere with cell signaling pathways, thereby preventing macrophages from becoming effectively activated [1;2]. As a result, these organisms are able to survive and successfully multiply within the otherwise hostile intracellular milieu of macrophages.
L. donovani is the major causative agent of human visceral leishmaniasis. This disease is progressive and often fatal if untreated. Macrophages infected with L. donovani show a phenotype of impaired cell signaling and cell deactivation. For example, interferon-□ signaling through the Jak-Stat1 pathway [3] and mitogen-activated protein kinase signaling leading to iNOS induction and c-FOS expression are attenuated in leishmania infected cells [4]. This phenotype is reversed in cells that are incubated with the protein tyrosine phosphatase (PTP) inhibitor sodium orthovandate prior to infection [4]. The Src-homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) appears to be involved in the pathogenesis of leishmania infections [4-7]. In particular, SHP-1 has been shown to become activated in leishmania infected cells [4;6] and leishmania infection is attenuated under conditions of SHP-1 deficiency [7]. Moreover, it has recently been shown that the conventional anti-leishmanial agent used (sodium stibogluconate) is an inhibitor of SHP-1 [8].